Synthesis of cyanotricarboxylate compounds



Patented May 2, 1950 UNITED STATES fiATENT OFFICE SYNTHESIS OFCYANOTRICARBOXYLATE COMPOUNDS Donald T. Warner and Owen A. Moe,Minneapolis,

Minn, assignors to General Mills, Inc., a corpcration of Delaware NoDrawing. Application October 4, 1948, Serial No. 52,794

Claims.

00 Oalk R--O O Oalk 2 (DH-ON C O0alk where alk represents an alkylgroup, and R is an alkyl group containing from two to twenty carbonatoms.

These compounds can be readily hydrolyzed to tetracarboxylic acids,which in turn can be decarboxylated to yield substituted pimelic acids.

These cyanotricarboxylate compounds may be prepared by thecondensation-reduction reaction of cyanoacetic ester andgam1na,gamma-dicarbalkoxy-gamma-alkyl butyraldehyde.

The gamma,gamma-dicarbalkoxy-gamma-alkyl butyraldehyde employed in thiscondensation may be prepared as disclosed in our copencling applicationSerial No. 714,645, filed December 6, 1946, entitled Aldehydes, nowabandoned. According to that application, these aldehydes may beprepared by the condensation of an alkyl-substituted malonic ester withacrolein which results in the direct production of the desired aldehyde.The details of this condensation will be more fully apparent from theexamples herein.

The condensation reduction of the aldehyde to the cyanotricarboxylatecompounds of the present invention and the subsequent conversion of thecyanotricarboxylate compounds to substituted pimelic acid areillustrated by the following reaction which demonstrates the reaction ofethyl cyanoacetate with gamma,gamma-dicarbethoxygamma-ethylbutyraldehyde for the ultimate production of alpha-ethyl pimelic acid:

COOEt COOEt C2 Hs- OOOEt C2115- GOOEt (EH2 COOEt Hz 6H2 CHzCN 1H2 H0 CH2JHON OOEt HOE

OOOH OOOH OaHa-(J-OOOH JflGifis H: H2 H: -2 6H2 111: (5H2 HCOOH all:

The condensation reduction may be carried out in the presence of asuitable solvent such as ethanol, dioxane, and the like, in the presenceof a conventional hydrogenation catalyst, and. under hydrogen pressure.When the reduction is complete, the reaction mixture may be filtered andthe filtrate concentrated in vacuo.

cyanotricarboxylate compounds may be hydrolyzed directly to thesubstituted pimelic acids in acidic media.

The following examples will serve to illustrate the invention.

Example 1 An alcoholic solution containing 200 parts of absolute ethylalcohol, 0.04 part of sodium, and 75.1 parts of ethyl ethylmalonate' wascooled to Thereafter the residual oil may be dissolved in benzene and- 1C. Acrolein (23.5 parts) was added over a 45-minute period at such arate that the reaction temperature was maintained between C.-4 C. Thefinal reaction mixture was stirred for an additional hour in an ice bathand then placed in the refrigerator for a period of 14 hours. Afterstanding for 14 hours, the catalyst was neutralized by the addition ofone part of glacial acetic acid. The alcohol was removed by distillationunder diminished pressure. Theresidual oil was mixed with 400 parts ofbenzene and the benzene solution was extracted with water. The benzenesolution was then dried over anhydrous sodium sulfate and finallyremoved by distillation under diminished pressure. The residual oilwhich was subjected to fractional distillation under diminished pressureweighed 88.6 parts. Distillation yielded approximately 67 parts ofdistillate which was collected over the range of 60-100 C. at 0.2 mm.The very viscous residue weighed 19 parts. The distillate was subjectedto another distillation under diminished pressure and five fractionswere obtained. The first fraction which was collected at 47454 C. at 0.1mm. weighed 7 parts and proved to be substantially ethyl ethylmalonate.The second fraction which was collected at 54-70 C. at 0.08 mm. weighingapproximately 6 parts was presumably a mixture of the unreacted malonicester and the desired aldehyde compound. The third fraction which wascollected at 70-75 C. at 0.07 mm. weighed parts and had a 11. 1.4372.The fourth fraction which was collected at 75-75.5 C. at 0.07 mm.weighed approximately 19 parts and had a c. 1.4386. Sample 5 which wascollected at 75.5-77 C. at 0.07 mm. weighed approximately 16 parts andhad a 11. 1.4394. The last three fractions, 3, 4, and 5, proved to besubstantially pure gamma,gamma-dicarbethoxycaproaldehyde. The aldehyde,compound was characterized as the 2,4-dinitrophenylhydrazone which was.prepared in the conventional manner. The purified dinitrophenylhydrazoneof gamma,- gamma dicarbethoxy caproaldehyde melted at 100.5101. 5? C.

24.4 g. of gamma-ethyl-gamma,gamma-dicarbethoxy butyraldehyde(gammagamma dicarbethoxy caproaldehyde) were dissolved in 50 ml. ofabsolute ethanol and 12.5 g. of ethyl cyanoac tate and 1.2 g. of glacialacetic acid were added. The resulting reaction mixture was cooled to 8C. when 0.4 g. of piperidine was added with shaking over a 5-minuteperiod. Then 1.2 g. of 5% palladium on charcoal was added and thehydrogenation was started at -50 pounds hydrogen pressure. The reductionwas substantially complete after a 3-hour period. The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo. Theresidue was dissolved in benzene and treated as previously described.Distillation of the reaction product under diminished pressure yieldedthree fractions. The first fraction was discarded and the second (main)fraction was collected at 156-163 C'. at 0.12 mm. n 1.4489. The thirdfraction was collected at 163-177 C. at 0.15-0.25 mm. 12 1.4520. Thelast two fractions were combined and subjected to redistillation underdiminished pressure and the desired fraction was collected at 145-l47 C.at 0.07 mm. 11 1.4482.

Five and four-tenths gram of the redistilled product were mixed with 25m1. of sodium hydroxide solution (4.1 g. sodium hydroxide). Theevolution of ammonia had ceased after a refluxing period of 44 hours.The reaction mixture was cooled, filtered and acidified withhydrochloric acid. The precipitated inorganic salts were removed byfiltration. The filtrate was concentrated in vacuo to yield a residualoil which solidified. The crude product thus obtained melted at 168-173C. with decomposition. When this tetracarboxylic acid was recrystallizedfrom benzene in ether mixture it melted at l70-171 C. with decomposition(neutral equivalent calculated at 69.0, found 70.5). One and one-tenthgram of the above tetracarboxylic acid was decarboxylated at 190 C. Whenthe evolution of carbon dioxide had ceased the resulting alpha-ethylpimelic acid weighed 0.74 g. The alpha-ethyl pimelic acid wascharacterized as the dianilide which melted at ISO-161 C. afterpurification.

Example 2 150 parts of absolute ethanol were reacted with 0.1 part ofmetallic sodium. When the sodium had reacted, 114.1 parts of diethyldecylmalonate were added and the solution was cooled to 0 C. To the coldsolution, 23.5 parts of acrolein were added at such a rate that thetemperature remained between 0 and +5 C. The reaction mixture was cooledat +3 C. for an additional 60 hours. The catalyst was then neutralizedby the addition of one part of glacial acetic acid, and

the reaction mixture was concentrated in vacuoon a water bath. Theresidual oil was dissolved in benzene, and the solution extracted withwater, after which the benzene solution was driedover anhydrous sodiumsulfate. 7 After filtering the sodiumsulfate, the benzene was removed byevaporation in'vacuo. The residual oil was subjected to distillation atapproximately 0.5 mm. to remove the excess diethyl decylmalonate. Thecrude aldehyde compound was obtained as a residue weighing 99.0 parts,11, 1.4542.

51.9 parts of crude aldehydo compound (gamma-decyl-gamma,gamma-dicarbethoxy butyraldehyde) were dissolved in 40 parts of 95%ethanol. 1.5 parts of glacial acetic acid and 20.3 parts of ethylcyanoacetate were added. The solution was cooled to 8 C. and 0.5 partsof piperidine were added in small portions. When the addition wascomplete, 1.4 parts of 5% palladium on charcoal were introduced; and themixture was hydrogenated at an initial pressure of 37 pounds ofhydrogen. Approximately of the theoretical hydrogen was absorbed in a20-hour period. The catalyst was removed by filtration and the filtratewas concentrated to a syrup. This syrup was dissolved in ether,'andthesolution was extracted with a 5% sodium chloride solution. The etherlayer was dried over anhy drous sodium sulfate, filtered, and the etherwas removed by evaporation on a steam bath. The residue was subjected todistillation at 0.7 mm. The main fraction boiled at 205-218/0.7 1pm., 111.4534. Redistillation yielded purified ethylalpha-cyano-epsilon,epsilon-dicarbethoxy hexadecanoate, B. P.=184-187 C./0..08 mm n 1.4531.

Example 3 The 1,4 addition of ethyl hexylmalonate to; acrolein wascarried out as follows:

Ethyl hexylmalonate (9.65 g.) was. added. to 3.0 ml. of absolute ethanolcontaining sodium ethoxide (prepared from 20 mg. of metallic. sodium)...The resulting reaction mixture was cooledto 0 C. and acrolein (2.24 g.)was added dropwise. The reaction mixture was cooled for 15 hours. Thecatalyst was neutralized with glacial acetic acid and concentration ofthe resulting solution.

in vacuo yielded a residual oil. A portion of this residual oilfwhentreated with 2,4-dinitrophenylhydrazine, yielded a2,4-dinitrophenylhydrazone melting at 86-87 C. This was theZA-dinitrophenylhydrazone ofgamma,gamma-dicarbethoxy-gamma-hexylbutyraldehyde.

Anal. Calcd. for C22Hs2OaN4: C, 54.96; H, 6.70. Found: C, 54.45; H,6.70.

0.1 mole of the crude gamma,gam1na-dicarbethoxy-gamma-hexylbutyraldehydewas dissolved in 50 cc. of absolute ethanol. To the resulting alcoholicsolution there was added 0.1 mole (11.3 g. ofethyl cyanoacetate and 1cc. of glacial acetic acid). The resulting solution was cooled to 10 C.and 0.5 g. of piperidine was added in small portions. When the additionof piperidine was complete, 1 g. of palladium on charcoal wasintroduced, and the mixture was hydrogenated at an initial pressure of40 pounds of hydrogen. After three hours the reduction was substantiallycomplete and the catalyst was removed by filtration. The resultingfiltrate was concentrated in vacuo. The condensation-re duction product,namely ethyl-alpha-cyano-epsilon, epsilon-dicarbethoxy-dodecanoate wasobtained as a very viscous oil.

Example 4 11.5 g. of ethyl hexadecylmalonate were dissolved in 50 cc. ofabsolute ethanol. A solution of sodium ethoxide (0.04 g. of sodium incc. of absolute ethanol) was added. The resulting reaction mixture wascooled to 5 C. Acrolein .7 g.) was added dropwise. The temperature ofthe reaction increased to 9 C. After stirring at 5 C. for a period ofthree hours, the reaction mixture was neutralized by the addition of therequisite quantity of glacial acetic acid. The ethanol was removed byconcentration in vacuo and thegamma,gamma-dicarbethoxy-gammahexadecylbutyraldehyde was obtained as aviscous oil. A portion of this oil was mixed with2,4-dinitrophenylhydrazine in a conventional manner and the resultinghydrazone was obtained as viscous oil which solidified on standing.Recrystallization from ethanol yielded the 2,4-dinitrophenylhydrazonemelting at 60-63 C.

0.1 mole of the crude gammagamma-dicarbethoxy gammahexadecylbutyraldehyde was dissolved in 50 cc. of absolute ethanol. Tothe resulting alcoholic solution there was added 11.3 g. (0.1 mole) ofethyl cyanoacetate and 1 cc. glacial acetic acid. The resulting solutionwas cooled to 5 C. and 0.4 g. of piperidine was added in portions. Whenthe addition of piperidine was complete, 1 g. of 5% palladium oncharcoal was added and the mixture was hydrogenated at an initialpressure of 33.8 pounds. After approximately two hours, the reductionwas complete and the catalyst was removed by filtration and the filtratewas concentrated in vacuo. The resulting condensation-reduction productwas obtained as a very viscous oil.

It is apparent that numerous variations are possible within the scope ofthe invention. Thus it has been shown that the alkyl substituent on themalonic ester may be varied from two to sixteen carbon atoms in thespecific examples set forth. It is also possible to use higher alkylsubstituents up to the C20 substituents and higher. Since, however, oneof the most practical ways of forming the substituted malonic esters(Floyd and Miller, J. A. C. 8., vol. 69, p. 2354 (1947)) involves thereaction of a low aliphatic ester of a fatty acid with an oxalate ester,the resultant alkyl substituent is two carbon atoms shorter than thefatty acid from which it is derived, and accordingly it is preferred notto employ alkyl substituents having more than sixteen carbon atoms inview of the scarcity of fatty acids from which such malonic esters maybe derived. It will be apparent, however, that if higher alkylsubstituents are desired, they can be obtained from the less readilyavailable fatty acids having suitable chain lengths. There are, ofcourse, other methods of preparing the alkyl-substituted malonic esters,and if desired, these may be employed.

Numerous variations are likewise possible in the conditions for thecondensation reduction. Thus any conventional hydrogenation catalystsuch as platinum, palladium, Raney nickel, and the like, may be used.Hydrogen pressures are capable of considerable variation, but, ingeneral, pressures between one and five atmospheres are suitable.Likewise temperature conditions may be varied, and, in general, atemperature range of from 20-50 C. is desirable. The time periodslikewise vary depending upon the compounds being treated, the catalystemployed, the solvent used, and the like. In general, it will be foundthat a time period of two to forty hours is suitable. In general thehydrogenation proceeds more readily in the presence of ethanol as thesolvent than it does in the presence of dioxane. Likewise the timeperiod is shorter where the substituent on the malonic group is a lowalkyl group than it is when this substituent is a long chain aliphaticgroup. Variations are likewise possible in the alkyl groups used as theesterifying groups for the malonic acid and also for the cyanoaceticacid. In general, however, it is preferred that these alkyl groupscontain from one to four carbon atoms. It will be apparent that othervariations in the process are also possible without departing from thespirit of the invention.

The present application is a continuation-inpart of our copendingapplication, Serial No. 755,708, filed June 17, 1947, entitled Synthesisof cyanotricarboxylate compounds, now Patent No. 2,468,352.

We claim as our invention:

1. Cyanotricarboxylate compounds having the formula:

OOOelk -GOOa1k C HEON where all: represents an alkyl group containingfrom 6 to 20 carbon atoms.

2. Cyanotricarboxylate compounds having the formula C O Oalk R- O O OalkEH2 5H1 HON OOBlk in which all; represents an alkyl group, and R is 5.7Cyanotricarboxylate compound having the an aliphatic hydrocarbon groupcontaining from formula 7 two to twenty carbon atoms. 7 000E;

'3. Cyanotricarboxylate compound having the formula CmHaa-(E-O O 0 Et H20 o om H: (mire-000m H,

on, 10 HON I H2 0 0 Et cm DONALD T. WARNER. (lgHcN OWEN A. MOE. GOOEtREFERENCES CITED 4. CyanotricarboxyIate compound having the g z gai gare of record m the formula UNITED STATES PATENTS (00m Number Name Date2 150 154 Cope Mar. 14 1939 o H -0o0 1 H E 2,176,018 Cope Oct. 10, 1939OTHER REFERENCES 2 v Zelinsky et a1., Ber. Deut. Chem., Vol. 29 p. 730

(1896). HON Zelinsky et aL, Beilstein (Handbuch, 4th ed),

(m vol. II, p. 869 (1920).

1. CYANOTRICARBOXYLATE COMPOUNDS HAVING THE FORMULA: 